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1. Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study

Author

van den Berg, Leonard H, Rothstein, Jeffrey D, Shaw, Pamela J, Babu, Suma, Benatar, Michael, Bucelli, Robert C, Genge, Angela, Glass, Jonathan D, Hardiman, Orla, Libri, Vincenzo, Mobach, Theodore, Oskarsson, Björn, Pattee, Gary L, Ravits, John, Shaw, Christopher E, Weber, Markus, Zinman, Lorne, Jafar-nejad, Paymaan, Rigo, Frank, Lin, Luan, Ferguson, Toby A, Gotter, Anthony L, Graham, Danielle, Monine, Michael, Inra, Jennifer, Sinks, Susie, Eraly, Satish, Garafalo, Steve, and Fradette, Stephanie

Published
2024
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2. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Author

Benatar, Michael, Wuu, Joanne, McHutchison, Caroline, Postuma, Ronald B, Boeve, Bradley F, Petersen, Ronald, Ross, Christopher A, Rosen, Howard, Arias, Jalayne J, Fradette, Stephanie, McDermott, Michael P, Shefner, Jeremy, Stanislaw, Christine, Abrahams, Sharon, Cosentino, Stephanie, Andersen, Peter M, Finkel, Richard S, Granit, Volkan, Grignon, Anne-Laure, Rohrer, Jonathan D, McMillan, Corey T, Grossman, Murray, Al-Chalabi, Ammar, Turner, Martin R, Arias, Jalayne, Boeve, Bradley, Dave, Kuldip, Ferguson, Toby, Floeter, Mary-Kay, Rohrer, Jonathan, Gendron, Tania, Gubitz, Amelie, Kaufman, Petra, Le Ber, Isabelle, Lee, Suzee, Malaspina, Andrea, McMillan, Corey, Nicholson, Katie, Postuma, Ronald, Robinson, Richard, Ross, Christopher, Tatton, Nadine, Thakur, Neil, Turner, Martin, and Weishaupt, Jochen

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Neurodegenerative, Dementia, Genetics, Alzheimer's Disease, Rare Diseases, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), ALS, Acquired Cognitive Impairment, Biotechnology, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Neurological, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Asymptomatic Diseases, Frontotemporal Dementia, Humans, Neurodegenerative Diseases, neurodegeneration, amyotrophic lateral sclerosis, pre-symptomatic, disease prevention, First International Pre-Symptomatic ALS Workshop, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Published
2022

3. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study

Author

Benatar, Michael, Wuu, Joanne, Andersen, Peter M., Bucelli, Robert C., Andrews, Jinsy A., Otto, Markus, Farahany, Nita A., Harrington, Elizabeth A., Chen, Weiping, Mitchell, Adele A., Ferguson, Toby, Chew, Sheena, Gedney, Liz, Oakley, Sue, Heo, Jeong, Chary, Sowmya, Fanning, Laura, Graham, Danielle, Sun, Peng, Liu, Yingying, Wong, Janice, and Fradette, Stephanie

Published
2022
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4. Correction to: Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study

Author

Benatar, Michael, Wuu, Joanne, Andersen, Peter M., Bucelli, Robert C., Andrews, Jinsy A., Otto, Markus, Farahany, Nita A., Harrington, Elizabeth A., Chen, Weiping, Mitchell, Adele A., Ferguson, Toby, Chew, Sheena, Gedney, Liz, Oakley, Sue, Heo, Jeong, Chary, Sowmya, Fanning, Laura, Graham, Danielle, Sun, Peng, Liu, Yingying, Wong, Janice, and Fradette, Stephanie

Published
2022
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5. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Miller, Timothy M, Cudkowicz, Merit E, Andrews, Jinsy A, Hesters, Adele, Kermorvant, Hugo, Lacomblez, Lucette, Forestier, Nadine Le, Lenglet, Thimotée, Retail, Maryvonne, Ruiz Del Mar Amador, Maria, Salachas, François, Shotar, Eimad, Sourour, Nader, Babu, Suma, Dorst, Johannes, Froehlich, Elke, Fromm, Andrea, Kandler, Katharina, Langer, Eva, Leichtle, Sarah, Ludolph, Albert, Mayer, Kristina, Michels, Sebastian, Raubold, Sabine, Benatar, Michael, Schuster, Joachim, Weiland, Ulrike, Wiesenfarth, Maximilian, Witzel, Simon, Calvo, Andrea, Canosa, Antonio, Casale, Federico, Chiò, Adriano, Fuda, Giuseppe, Grassano, Maurizio, McDermott, Christopher J, Marchese, Giulia, Moglia, Cristina, Palumbo, Francesca, Salamone, Paolina, Ajiki, Takahiro, Akasaka, Aya, Ando, Masahiro, Arata, Hitoshi, Asuka, Kitamura, Baba, Kosuke, Cochrane, Thos, Bekku, Goichi, Chiba, Tomoya, Date, Yugaku, Eriko, Takeuchi, Hashiguchi, Akihiro, Hatatori, Ritsuko, Hayano, Eri, Hayashi, Yuto, Higashi, Keiko, Higuchi, Eriko, Chary, Sowmya, Hiramatsu, Yu, Horikawa, Rui, Ikenaka, Kensuke, Ishiura, Hiroyuki, Ito, Daisuke, Kawai, Sachiko, Kikuchi, Junko, Kuzuyama, Haruko, Li, Xuehong, Matsumoto, Chika, Chew, Sheena, Matsuura, Eiji, Michizono, Kumiko, Mitsui, Jun, Mitsutake, Akihiko, Mochizuki, Hideki, Nagamatsu, Akemi, Nagano, Seiichi, Nakamura, Tomonori, Naruse, Hiroya, Ogasawara, Asuka, Zhu, Han, Okada, Kensuke, Okamoto, Yuji, Okuno, Tatsusada, Oyama, Satoshi, Ozono, Tatsuhiko, Sakiyama, Yusuke, Sakuishi, Kaori, Seki, Morinobu, Shibata, Shota, Shimizu, Mikito, Wu, Fan, Takahata, Katsunori, Takahito, Yoshizaki, Takashima, Hiroshi, Takeichi, Hiroko, Tashiro, Yuichi, Toda, Tatsushi, Tomizu, Yuki, Tomoya, Wadayama, Ujiakira, Nishiike, Yashita, Daiki, Nestorov, Ivan, Al-Chalabi, Ammar, Alix, James, Bangalore, Priyadarshini, Blackburn, Daniel, Chiwera, Theresa, Clegg, Rosie, Collins, Alexis, Cooper-Knock, Jonathan, Emery, Anna, Franklin, John, Genge, Angela, Graham, Danielle, Green, Louisa, Harvey, Callum, Hobson, Esther, Islam, Mahjabim, Jenkins, Thomas Michael, Kazoka, Mbombe, Kelly, Gillian, Korley, Mercy, Madarshahaian, Daniel, Mayl, Keith, Sun, Peng, McDermott, Christopher John, Radford, Alex, Shaw, Christopher, Shaw, Pamela J, Sidebottom, Joe, Smart, Lynne, Sreedharan, Jemeen, Stone, Ben, Tsironis, Theocharis, Tuddenham, Lee, McNeill, Manjit, Verber, Nick, Wollff, Helen, Young, Stacy, Zis, Panagiotis, Adamo, Ashley, Ahmed, Arubah, Ajroud-Driss, Senda, Alameda, Gustave, Arcila-Londono, Ximena, Fanning, Laura, Baird, Candy, Bazan, Tracy, Berry, James, Bordeau, Jane, Bradford, Wendy, Brook, Nyda, Brown, Lauren, Bucelli, Robert C, Ferguson, Toby A, Buckner, Katherine, Budler, Michael W, Burba, Lindita, Burke, Katherine, Calhoun, Ashley D, Campbell, Sarah, Carey, Judith, Caristo, Irys B, Carty, Simon, Chan, Emmanuel, Fradette, Stephanie, Chaudhry, Vinay, Chen, Ricky, Chow, Saephanh, Clawson, Lora L, Clemens, Mitchell, Cloninger, Suzann E, Coleman-Wood, Krista, Cooper, Thomas N, Cummings, Arlena, Daniels, Jacquelyn, VALOR, DeSaro, Pamela, DeWitt, Michelle, Dedi, Brixhilda, Dempsey, Debbie, Denny, Carol, Doherty, Jenna, Doherty, Leana, Donahue, Megan, Doyle, Michael, Duncan, Jessie, Group, OLE Working, Elman, Lauren, Eloge, Christine M, Echiti, Desirae R, Ferrey, Dominic, Fournier, Christina, Fukumura, Yuriko, Gallagher, Katherine, Garaycoa, Jessica, Garrett, Mark, Gibson, Richard L, Beullens, Lien, Gifford, Ryan, Glass, Jonathan D, Gogol, Danuta, Golden, Shea, Gonzalez, Alexa, Goodman, Ira, Goolsby, Christopher, Goslin, Kimberly, Goulbourne, Michael, Granit, Volkan, Claeys, Kristl, Grignon, Anne-Laure, GuhaRay, Adreeja, Guide, Debra, Gundogdu, Melek Betul, Gutierrez, Gil, Hastings, Debbie, Hayzen, Colleen, Herzog, Hilary, Holloway, Raegan, Jacobs, Gabriel, Claeys, Thomas, Jacobsen, Bill, James, Virginia, Jenkins, Liberty, Jockel-Balsarotti, Jennifer, Johnson, Linda Carol, Jose, Sunil, Joslin, Benjamin, Karanja, Elizabeth, Katz, Jonathan, Keener, Anthony, Couwelier, Goedele, Kittle, Gale, Klein, Sara, Kreple, Collin, Rebecca, Rebecca, Kuenzler, Kuenzler, Kusnir, Jorge, Labbe, Kristen, Lachica-Encinas, Nicolet, Ladha, Shafeeq, Leimer, Lesli, D'Hondt, Ann, Levy, Michael, Levy, Wendy, Li, Yingji, Likanje, Marie-France, Livigni, Rebecca, Locatelli, Eduardo, Luppino, Sarah, Malcolm, Amber, Maragakis, Nicholas, Marin, Horia, Debien, Elisa, Markowitz, Clyde, Markway, Jesse, McCaffrey, Alexandra, McCoy, Arita, McCoy Gross, Kelly, Mehta, Kush, Meyer, Robert, Milan, Jennifer, Miller, Timothy, Miller, Robert G, de Keersmaecker, Sebastiaan, Morales, Francisco, Mosmiller, Elizabeth, Mott, Donovan, Moulton, Kelsey, Murphy, Christine A, Negron, Tirso, Nelson, Cassandra, Newman, Daniel S, Nissinen, Janne Kristoffer, Norman, Andrew, Della Faille, Laetitia, Ohkubo, Takuya, Olney, Nicholas, Ortiz, Natasha, Oskarsson, Bjorn, Pace, Mitchell, Packard, Kathleen, Padgett, Denny, Paganoni, Sabrina, Paredes, Maria E, Parker, Elizabeth, Delmotte, Koen, Partlow, Ann, Pattee, Gary L, Paulett, Jany, Pelot, Antoinette, Pfeifer, Kyle M, Pijanowski, Olivia, Pioro, Erik, Polak, Meraida, Prakash, Ahalya, Previte, Rosemarie, Depoortere, Sofie, Pukenas, Bryan, Quinn, Colin, Ravits, John, Razavi, Ryan, Regan, Tyler, Riley, Kristen M, Roth, Heather, Sanders, Danica, Scalia, Jennifer, Schmidt, Emma, de Velder, Laura, Schwen, Edward, Shah, Jaimin, Shah, Stuti, Shefner, Jeremy, Sheldon, Danielle, Simmons, Karon, Singh, Navneet K, Singleton, Jessica, Smiley, Richard, Smith, William B, Dobbels, Laurens, Smith, Sean, Sotirchos, Elias, Sorenson, Eric, Staff, Nathan, Steele, Julie, Steijlen, Kara, Stirrat, Taylor, Stoica, George S, Strong, Stephanie, Sufit, Robert, Sobue, Gen, Gijs, Jeroen, Sultze, Jane, Swartz, Amy, Szymanski, April, Tay, Anna, Thakore, Nimish, Thiessen, Diana, Thotala, Sukrutha, Trudell, Randall G, Turcotte, Nicole, Turner, Michelle, Horckmans, Simon, Uchil, Alpa, Upadhyay, Vihar, Usman, Uzma, Vallis, Anne, Vaporean-Bussey, Danielle, Vladimirova, Valentine, Weber, Harli, Winbigler, Jennifer, Wojanowski, Heather, Wulf, Charlie, Lamaire, Nikita, Yasek, Julia, Yoo, Stephanie, Zivalic, Hannah, Cole, Alexandra, File, Greta, Foate, Jeremy, Mason, Deborah, Newton, Susan, Roberts, Stephen, Sellwood, Cory Dean, Liessens, Hannelore, Swan, James, Werno, Anja, Zhong, Cathy, Masrori, Pegah, Nysten, Celine, Schotte, Caroline, Serrien, Anouk, Swinnen, Bart, Tilkin, Petra, van Daele, Sien, Van Damme, Philip, Vynckier, Jan, Wouters, Anke, Abrahao, Agessandro, Angle, Mark, Badawy, Mohamed, Berube, Maxime, Bertone, Vanessa, Cooper, Sarah Marie, Dobrowolski, Peter, Fong, Helen, Hannouche, Matthew, Hartley, Denise, Hogan, Michael, Johnston, Wendy, Khalfallah, Yousra, Korngut, Lawrence, Kroetsch, Gina, Letourneau, Justin, Magnussen, Claire, Martinez, Jose, Massie, Rami, Mobach, Theodore, Mookshah, Jahan, Ozelsel, Timur, Parks, Andrea, Petrillo, Janet, Pfeffer, Gerald, Ludolph, Albert C, Pham, Shirley, Phung, Liane, Shiungsun, Rodney, Pi-Shan, Li, Santos, Denizart, Salmon, Kristiana, Saunders, Natalie, Sembinelli, Dylan, Tymkow, Kelsey, Wong, Berchman, Zinman, Lorne, Karlsborg, Merete, Pedersen Lomholt, Therese, Nilsson, Sigrid, Salvesen, Lisette, Skov, Pernille, Svenstrup, Kristen, Bruneteau, Gaelle, Calerencon, Frederic, and Guimaraes Costa, Raquel

Subjects
Adult, drug effects [Recovery of Function], Spinal, Oligonucleotides, blood [Neurofilament Proteins], administration & dosage [Oligonucleotides, Antisense], tofersen, Injections, blood [Amyotrophic Lateral Sclerosis], pharmacology [Oligonucleotides, Antisense], Superoxide Dismutase-1, Double-Blind Method, Neurofilament Proteins, Humans, ddc:610, Antisense, Injections, Spinal, Biomarkers, Recovery of Function, Amyotrophic Lateral Sclerosis, Oligonucleotides, Antisense, blood [Biomarkers], drug therapy [Amyotrophic Lateral Sclerosis], therapeutic use [Oligonucleotides, Antisense], SOD1 protein, human, General Medicine, genetics [Superoxide Dismutase-1], genetics [Amyotrophic Lateral Sclerosis], cerebrospinal fluid [Biomarkers], cerebrospinal fluid [Superoxide Dismutase-1], cerebrospinal fluid [Amyotrophic Lateral Sclerosis]
Abstract

The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Published
2022

8. Design of a Phase 3, Randomized, Placebo-controlled Trial of Tofersen Initiated in Clinically Pre-symptomatic SOD1 Mutation Carriers with a Longitudinal Natural History Run-in (2285)

Author

Benatar, Michael, primary, Wuu, Joanne, additional, Andersen, Peter M., additional, Andrews, Jinsy, additional, Bucelli, Robert C., additional, Otto, Markus, additional, Ferguson, Toby A., additional, Chen, Weiping, additional, Fanning, Laura, additional, Graham, Danielle, additional, Sun, Peng, additional, Liu, Yingying, additional, Wong, Janice, additional, and Fradette, Stephanie, additional

Published
2021
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9. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Miller, Timothy, Cudkowicz, Merit, Shaw, Pamela J., Andersen, Peter M., Atassi, Nazem, Bucelli, Robert C., Genge, Angela, Glass, Jonathan, Ladha, Shafeeq, Ludolph, Albert L., Maragakis, Nicholas J., McDermott, Christopher J., Pestronk, Alan, Ravits, John, Salachas, Francois, Trudell, Randall, Van Damme, Philip, Zinman, Lorne, Bennett, C. Frank, Lane, Roger, Sandrock, Alfred, Runz, Heiko, Graham, Danielle, Houshyar, Hani, McCampbell, Alexander, Nestorov, Ivan, Chang, Ih, McNeill, Manjit, Fanning, Laura, Fradette, Stephanie, Ferguson, Toby A., Miller, Timothy, Cudkowicz, Merit, Shaw, Pamela J., Andersen, Peter M., Atassi, Nazem, Bucelli, Robert C., Genge, Angela, Glass, Jonathan, Ladha, Shafeeq, Ludolph, Albert L., Maragakis, Nicholas J., McDermott, Christopher J., Pestronk, Alan, Ravits, John, Salachas, Francois, Trudell, Randall, Van Damme, Philip, Zinman, Lorne, Bennett, C. Frank, Lane, Roger, Sandrock, Alfred, Runz, Heiko, Graham, Danielle, Houshyar, Hani, McCampbell, Alexander, Nestorov, Ivan, Chang, Ih, McNeill, Manjit, Fanning, Laura, Fradette, Stephanie, and Ferguson, Toby A.

Abstract

Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. Results: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. Conclusions: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis

Published
2020
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10. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Miller, Timothy, primary, Cudkowicz, Merit, additional, Shaw, Pamela J., additional, Andersen, Peter M., additional, Atassi, Nazem, additional, Bucelli, Robert C., additional, Genge, Angela, additional, Glass, Jonathan, additional, Ladha, Shafeeq, additional, Ludolph, Albert L., additional, Maragakis, Nicholas J., additional, McDermott, Christopher J., additional, Pestronk, Alan, additional, Ravits, John, additional, Salachas, François, additional, Trudell, Randall, additional, Van Damme, Philip, additional, Zinman, Lorne, additional, Bennett, C. Frank, additional, Lane, Roger, additional, Sandrock, Alfred, additional, Runz, Heiko, additional, Graham, Danielle, additional, Houshyar, Hani, additional, McCampbell, Alexander, additional, Nestorov, Ivan, additional, Chang, Ih, additional, McNeill, Manjit, additional, Fanning, Laura, additional, Fradette, Stephanie, additional, and Ferguson, Toby A., additional

Published
2020
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11. Tofersen, a SOD1 Antisense Oligonucleotide in Participants with ALS – Results From a Multiple Dose Study (657)

Author

Cudkowicz, Merit, primary, Miller, Timothy, additional, Shaw, Pamela, additional, Bennett, C. Frank, additional, Lane, Roger, additional, Chang, Ih, additional, Liu, Yingying, additional, Chen, Weiping, additional, Nestorov, Ivan, additional, Graham, Danielle, additional, Fanning, Laura, additional, McNeill, Manjit, additional, Fradette, Stephanie, additional, and Ferguson, Toby, additional

Published
2020
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13. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

Author

De Vivo, Darryl C., primary, Bertini, Enrico, additional, Swoboda, Kathryn J., additional, Hwu, Wuh-Liang, additional, Crawford, Thomas O., additional, Finkel, Richard S., additional, Kirschner, Janbernd, additional, Kuntz, Nancy L., additional, Parsons, Julie A., additional, Ryan, Monique M., additional, Butterfield, Russell J., additional, Topaloglu, Haluk, additional, Ben-Omran, Tawfeg, additional, Sansone, Valeria A., additional, Jong, Yuh-Jyh, additional, Shu, Francy, additional, Staropoli, John F., additional, Kerr, Douglas, additional, Sandrock, Alfred W., additional, Stebbins, Christopher, additional, Petrillo, Marco, additional, Braley, Gabriel, additional, Johnson, Kristina, additional, Foster, Richard, additional, Gheuens, Sarah, additional, Bhan, Ishir, additional, Reyna, Sandra P., additional, Fradette, Stephanie, additional, and Farwell, Wildon, additional

Published
2019
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14. Neurofilament as a potential biomarker for spinal muscular atrophy

Author

Darras, Basil T., primary, Crawford, Thomas O., additional, Finkel, Richard S., additional, Mercuri, Eugenio, additional, De Vivo, Darryl C., additional, Oskoui, Maryam, additional, Tizzano, Eduardo F., additional, Ryan, Monique M., additional, Muntoni, Francesco, additional, Zhao, Guolin, additional, Staropoli, John, additional, McCampbell, Alexander, additional, Petrillo, Marco, additional, Stebbins, Christopher, additional, Fradette, Stephanie, additional, Farwell, Wildon, additional, and Sumner, Charlotte J., additional

Published
2019
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15. Association of Phosphorylated Neurofilament Heavy Chain (pNF-H) Levels With Motor Function Achievement in Individuals With Spinal Muscular Atrophy (SMA) Treated With Nusinersen (S27.009)

Author

Sumner, Charlotte J., primary, Darras, Basil T., additional, Muntoni, Francesco, additional, Crawford, Thomas O., additional, Finkel, Richard S., additional, Mercuri, Eugenio, additional, De Vivo, Darryl C., additional, Oskoui, Maryam, additional, Tizzano, Eduardo, additional, Ryan, Monique M., additional, Zhao, Guolin, additional, Petrillo, Marco, additional, Stebbins, Christopher, additional, Fradette, Stephanie, additional, and Farwell, Wildon, additional

Published
2019
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16. Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results From the Phase 2 NURTURE Study (S25.001)

Author

De Vivo, Darryl C., primary, Topaloglu, Haluk, additional, Swoboda, Kathryn J., additional, Bertini, Enrico, additional, Hwu, Wuh-Liang, additional, Crawford, Thomas O., additional, Foster, Richard, additional, Bhan, Ishir, additional, Fradette, Stephanie, additional, Farwell, Wildon, additional, and Reyna, Sandra P., additional

Published
2019
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18. Soft touch.

Author

Fradette, Stephanie

Published
2018

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